Regulation of Mitochondrial Biogenesis and Function by DsbA-L in the Liver

摘要 肝细胞中的线粒体在维持全身能量代谢和正常 肝脏的功能。线粒体功能受损与各种代谢疾病密切相关， 肥胖、胰岛素抵抗和脂肪肝。然而，确切的基本机制仍有待于 充分阐明。填补这一重大知识空白将产生关于其机制的新信息 线粒体功能障碍相关的肝脏疾病、胰岛素抵抗和2型糖尿病。 我们目前的研究重点是二硫键-A的功能作用和作用机制 氧化还原酶样蛋白（DsbA-L）。我们最近发现，DsbA-L表达显著减少， 肥胖人类受试者和饮食诱导的肥胖小鼠的肝脏。此外，功能丧失和获得研究 表明DsbA-L是线粒体完整性和功能的关键调节因子，其在肝脏中的缺乏起着重要作用。 在肥胖引起的脂肪肝和代谢功能障碍中起重要作用。在本研究中，我们将使用 分子和细胞的方法以及敲除动物模型，以阐明调节机制， 线粒体的完整性和功能在生理和病理生理条件下。这项研究应该 揭示了肥胖、线粒体损伤和肝功能障碍之间的联系， 了解肥胖引起的胰岛素抵抗和代谢性疾病的机制。因此，在本发明中， 我们提出的研究应该提供关于DsbA-L生物学的有价值的信息， 抗肥胖和抗胰岛素抵抗疗法的靶点。

Abstract Mitochondria in hepatocytes play a major role in maintaining whole-body energy metabolism and normal function of the liver. Impaired mitochondrial function is closely associated with various metabolic diseases such as obesity, insulin resistance, and hepatosteatosis. However, the precise underlying mechanisms remain to be fully elucidated. Filling this major gap of knowledge will yield new information on the mechanisms underlying mitochondrial dysfunction-associated liver diseases, insulin resistance, and type 2 diabetes. Our current study focuses on the functional roles and mechanisms of action of the disulfide-bond-A oxidoreductase-like protein (DsbA-L). We recently found that DsbA-L expression is significantly reduced in the liver of obese human subjects and diet-induced obese mice. In addition, loss- and gain-of-function studies reveal that DsbA-L is a key regulator of mitochondrial integrity and function and its deficiency in the liver plays an important role in obesity-induced hepatosteatosis and metabolic dysfunction. In the current study, we will use molecular and cellular approaches as well as knockout animal models to elucidate the mechanisms regulating mitochondrial integrity and function under physiological and pathophysiological conditions. This research should shed new light on the link between obesity, mitochondrial impairment, and liver dysfunction and further our understanding of the mechanisms underlying obesity-induced insulin resistance and metabolic diseases. Thus, our proposed studies should provide valuable information on the biology of DsbA-L potentially being useful as targets of anti-obesity and anti-insulin resistance therapeutics.